Frontotemporal dementia (FTD) represents only 10-20% of all dementias, but remains important clinically because of its earlier age of onset compared to Alzheimer's disease (AD), and its characteristic attack on core human qualities ,e.g..compassion, insight and verbal communication. Treatment of FTD, as in AD, is more likely to succeed when applied in the early stages of the underlying pathology than in later stages, when symptoms appear and worsen. Detection of brain pathology is needed prior to these symptoms in order to develop and evaluate such treatments. We propose to use functional and structural magnetic resonance imaging (MRI) to detect brain network functional alterations, and subtle changes in cortical density in the frontal and anterior temporal lobes, in persons without dementia symptoms, but who are destined to develop FTD. The high likelihood of developing FTD is well-defined in identified subjects with mutations in the valosin-containing protein (VCP) gene on chromosome 9 associated with FTD, Paget's disease of bone, and inclusion-body myopathy. These persons will be tested to insure the absence of symptoms and typical cognitive impairments in FTD. Mutation carriers will be compared to non-carrier members of the same families. The first specific aim is to perform functional MRI studies to measure frontal and parietal activation during standard working memory and letter fluency tasks typically performed poorly in persons with early symptoms of FTD. We will also perform a control confrontation naming task, shown in preliminary studies to activate regions of the posterior temporal and occipital regions equally in VCP mutation carriers and in non-carriers. These data will be analyzed using advanced analytical and statisitical techniques, discriminant analysis and hierarchical clustering, to identify carriers most likely to develop future dementia. The second specific aim is to compare regional cortical density measured from three-dimensional structural images between VCP mutation carriers and non-carriers. We will combine the functional and structural measures with cognitive test results to refine our predictive model for dementia. These fundamental studies are expected to demonstrate brain network functional alterations and regionally decreased cortical density in rigorously-defined presymptomatic FTD. [unreadable] [unreadable] [unreadable]